Stereoisomers Stereoisomers have the same molecular formula and connectivity but differ in their orientation in 3-dimensional space. Enantiomers Enantiomers are compounds that are non-superimposable mirror images of each other. “Enantiomers” in Everyday Life… “Enantiomers” in Everyday Life… Figure eight knot – frequently used in climbing Chiral Carbon Atoms An sp3 hybridized carbon atom with four different substituents is chiral. Chiral atoms may be referred to as stereocenters, asymmetric centers or stereogenic centers. Which of these molecules has a chiral carbon? Chiral Carbon Atoms Chiral atoms are sometimes denoted with an asterisk (*). Solid wedge – substituent projecting forward Dashed wedge – substituent projecting backward Chiral Molecules If a molecule contains one or more chiral carbon atoms, and it does not have a plane of symmetry, it is a chiral molecule. Meso compounds contain chiral centers, but have a plane of symmetry so are achiral. Chiral Achiral Meso compound Chiral Molecules Lack a Plane of Symmetry Which of these molecules are chiral? Enantiomers Have Same Physical Properties Except Rotation of Plane Polarized Light Identical: Melting points, boiling points, solubility, polarity Spectral data (NMR, IR, MS, UV) Different: Enantiomers rotate plane polarized light in opposite directions of each other. (+): Rotation to the right (-): Rotation to the left Absolute configuration can not be assigned based on optical rotation alone. (R)-enantiomers can be (+) or (-), and (S)-enantiomers can be (+) or (-). Enantiomers Can Have Different Biological Activities The body is composed of many chiral molecules: proteins, peptides, carbohydrates, nucleic acids, lipids, so enantiomers are often recognized differently. (R)-carvone spearmint scent (S)-carvone caraway scent Olfactory receptors are chiral, as these enantiomers are recognized differently Everyday Analogy to Compare… You can pick up an achiral coffee mug with your chiral right hand or your chiral left hand similarly. You can not shake your chiral right hand with someone else’s chiral left hand efficiently. As the Number of Chiral Carbons in a Molecule Increases, So Does the Number of Possible Stereoisomers If a molecule has n chiral carbon atoms, there are 2n possible steroisomers, though there may be fewer due to symmetry. 2 chiral carbons 22 = 4 steroisomers * * Diasteromers Diastereomers are stereoisomers that are not enantiomers. Molecules with two or more chiral carbon atoms can have diasteromers. Ephedrine Pseudoephedrine Stimulant, appetite suppressant, decongestant Decongestant, stimulant Identify Chiral Carbons and Determine Number of Possible Stereoisomers Identify the chiral carbon atom(s) and determine the number of possible stereoisomers. Configuration and Conformation Configuration: Changing the configuration of a molecule requires bonds to be broken and reformed. A different configuration is a different molecule. (R)-configuration (S)-configuration Conformation: Changing the conformation of a molecule means rotating about single bonds. Conformations are interconvertible and are the same molecule. (R)-configuration in different conformations Some Drugs Are Marketed as Racemic Mixtures Ibuprofen NSAID Racemic mixture A racemic mixture is a 50:50 mixture of two enantiomers. (S)-Ibuprofen active (R)-Ibuprofen inactive Some Drugs Must be Administered as Single Enantiomers Due to Toxicity of Enantiomer L-Dopa D-Dopa Flip D-Dopa like a pancake, can see it’s the mirror image of L-Dopa L-Dopa Treatment of Parkinson’s disease D-Dopa Toxic Single Enantiomers Are Marketed For Some Drugs That Do Not Have a Toxic Enantiomer Mixture of enantiomers Single enantiomer Celexa® (citalopram oxalate) R- and S- enantiomers antidepressant / antianxiety selective serotonin reuptake inhibitor (SSRI) Lexapro® (escitalopram oxalate) S-enantiomer Considerations of single-enantiomer drugs: 1) Lower dose (only active enantiomer) 2) Potentially fewer side effects 3) More expensive Enantiomeric Compounds Can Have Drastically Different Biological Effects Levmetamfetamine Active ingredient in this OTC decongestant Enantiomeric Compounds Can Have Drastically Different Biological Effects (S)-methamphetamine CNS stimulant (R)-methamphetamine No CNS activity Pseudoephedrine and Ephedrine Are Now Regulated Pseudoephedrine Original Sudafed® active ingredient Ephedrine Decongestant, stimulant, appetite suppressant Stereochemical relationship between pseudoephedrine and ephedrine? Absolute configurations of these molecules? Pseudoephedrine and Ephedrine Are Now Regulated pseudoephedrine ephedrine (S)-methamphetamine FDA approved for ADHD, obesity Non-GMP laboratory… (GMP = Good manufacturing practice) Phenylephrine “New Formula” Sudafed® Enantiomeric Compounds Can Have Drastically Different Biological Effects (R)-thalidomide sedative, antiemetic prescribed for morning sickness 1957-1961 (S)-thalidomide potent teratogen Thousands of children born with birth defects Can not administer thalidomide as a single enantiomer drug because it isomerizes in vivo.